EP2899198B1 - Peptide synthétique pntx(19), compositions pharmaceutiques et utilisation - Google Patents

Peptide synthétique pntx(19), compositions pharmaceutiques et utilisation Download PDF

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Publication number
EP2899198B1
EP2899198B1 EP13831141.0A EP13831141A EP2899198B1 EP 2899198 B1 EP2899198 B1 EP 2899198B1 EP 13831141 A EP13831141 A EP 13831141A EP 2899198 B1 EP2899198 B1 EP 2899198B1
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EP
European Patent Office
Prior art keywords
peptide
pntx
pharmaceutical composition
pntx2
erectile
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German (de)
English (en)
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EP2899198A4 (fr
EP2899198A1 (fr
Inventor
Maria Elena DE LIMA PEREZ GARCIA
Carolina NUNES DA SILVA
Flávia DE MARCO ALMEIDA
Rosangela DA SILVA LOMEO
Paulo Sérgio LACERDA BEIRÃO
Fernanda SILVA TORRES
Adriano MONTEIRO DE CASTRO PIMENTA
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Universidade Federal de Minas Gerais
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Universidade Federal de Minas Gerais
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Priority claimed from BR102012020800A external-priority patent/BR102012020800A2/pt
Priority claimed from BR102013020574-5A external-priority patent/BR102013020574B1/pt
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
    • C07K14/43518—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from spiders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a synthetic polypeptide of 19 amino acids, called PnTx(19), constituted from the sequence of native toxin PnTx2-6 of the Phoneutria nigriventer spider. It also relates to pharmaceutical compositions containing such a peptide and to the use thereof in the treatment of erectile dysfunction and/or in potentiating the erectile function.
  • the venom of the Phoneutria nigriventer spider is rich in bioactive polypeptides with different pharmacological effects, acting chiefly in ion channels and receptors.
  • the predominant symptoms caused by its venom result from general hyper-excitability.
  • Nitric oxide (NO) a product from the hydrolysis of L-arginine by nitric oxide synthase (NOS), is an essential mediator of the erection process
  • NANC non-adrenergic-non-cholinergic nerves
  • GCs soluble cyclase guanylate
  • GMPc cyclic guanosine monophosphate
  • GMPc The formation of GMPc induces the decrease in the levels of intracellular calcium, leading to relaxation of the smooth muscle cells with a subsequent penial tumescence (TOTA et al., 2005). Erection ends due to the hydrolysis of the GMPc by the enzyme phosphodisesterase type 5 (( IGNARRO, L.J. et al. Biochem Biophys Res Commun., 170, 843-50, 1990 ; RAJFER, J. et al. N. Engl. J. Med. 326(2), 90-94, 1992 ; LEE, M.R. J. Biol. Chem. 272, 5063-5068, 1997 ; BIVALACQUA, T.J.et al. Trends Pharmacol. Sci., 21 (12), 484-489, 2000 ).
  • PDE-5 inhibitors such as sildenafil (Viagra), taladafil (Cialis® and vardenafil (Levitra®) ( MORELAND, R.B et al. Trends Endocrinol. Metab. 10(3), 97-104, 1999 ; PRIVIERO, F.B. et al Acta Pharmacol. Sin. 28(6), 751-755, 2007 ; LEITE, R. at al. Recent Pat. Cardiovasc. Drug Discov. 2(2), 119-132, 2007 ).
  • PDE-5 inhibitors are not efficient in the treatment of patient with vascular diseases, where the production of NO is impaired.
  • this toxin enabling the production of medicaments effective for patients with erectile dysfunction who may not be treated by the presently available medicaments.
  • PnTx2-6 refers to the stimulation of the release of cerebrocortical synaptosome glutamate of rat [SILVA, 2012 - com. Pessoal - SILVA, C. N. Análise da liberaç ⁇ o de L-glutamato de sinaptosomas de cortex cerebral de rato pela toxina PnTx2-6 da peciosha da aranha armadeira (Phoneutria nigriventer) (Analysis of the release of L-glutamate of from the cerebral cortex of rats by the toxin PnTx2-6 of the venom of the armed spider (Phoneutria nigriventer).
  • L-glutamate L-glutamate or L-glu
  • L-glu Glutamate
  • Glutamate is the main and most abundant excitatory neurotransmitter of the CNS on mammalians. It exerts a crucial role in mechanisms underlying the synaptic plasticity, which are part of the physiological bas of behavioral processes such as cognition and memory. L-glu also performs relevant functions in the development of the nervous system like formation, remodeling, elimination of synapses, migration, proliferation, neuronal differentiation, and cell death (( PRYBYLOWSKI, K. et al. J Biol Chem. 279, 9673-6, 1994 ; MCKINNEY, R.A.. Journal Physiology. 588 (1),107-116, 2010 ; MANENT, J.B., REPRESA, A.
  • glutamate can facilitate the penial erection by activating some cerebra areas that are involved in the control of erectile function line the paraventricular nucleus (PVN), the tegmented ventral area (VTA), the hippocampus, among others ( ARGIOLAS, A., MELIS, M.R.. Prog. Neurobiol. 47, 235-255, 1995 ; SONG, Y., RAJASEKARAN, M.
  • the concrete result of the peripheral action of the toxin on the erection refers to the relaxation of slices of the cavernous body when the toxin is applied directly onto this in vitro preparation (NUNES et al. 2010a; 2010b; 2012).
  • the modified synthetic peptide PnTx(19) which exhibits a short polypeptide chain of 19 amino acids, which enables one to obtain it easily for commercial purposes, providing the development of pharmaceutical compositions for use in the treatment of erectile dysfunction and/or in potentiating the erectile function.
  • this peptide induces release of glutamate in cerebrocortical synaptosomes of rats, stimulates the relaxation of slices of cavernous bodies of mice and rats, exhibits lower toxic effect with respect to the native toxin from which it is derived, and further does not exhibit cardiac toxicity, unlike Viagra present on the market. It is also effective in hypertensive animals and exhibits low immunogenicity.
  • the present invention comprises the peptide PnTx(19), NH3-GERRQYFWIAWYKLANSKK-COOH (SEQ ID NO.1), synthetized chemically by using the Fmoc/t-butyl strategy of synthesis on solid support ( MERRIFIELD, R. B. Solid-phase peptide synthesis. Adv. Enzymol. Relat. Areas Mol. Biol. (32), 221-296, 1969 ).
  • the peptide has 19 amino acid residues, is linear and was designed from the probable three-dimensional structure of the PnTx2-6 proposed after analysis for bioinformatics and molecular modeling studies.
  • Such pharmaceutical compositions are characterized by comprising a synthetic peptide and an excipient or a mixture of pharmaceutically acceptable excipients, wherein the peptide may be present either in the free from or coupled to controlled release systems.
  • the controlled release systems may include lyposomes, cyclodextrines, biodegradable polymers, capsules, micro- and nano-capsules, micro- and nano-particles, bolus preparations, osmotic pumps, diffusion devices, lypospheres, transdermal administration systems and/or liquids that, when subjected to changes in temperature, form a solid or a gel in situ.
  • the pharmaceutical compositions may be administered by the oral, topical, intramuscular, intravenous, subcutaneous, inhalation routes, or by implantable devices.
  • the synthetic peptide called PnTx(19) was partially designed by using the bioinformatics program PEPOP.
  • PEPOP bioinformatics program
  • the peptide PnTx(19) was purified by reversed-phase chromatography (HPLC ⁇ KTA Explorer 10).
  • the chromatographic profile presented in Figure 1 demonstrates the presence of synthesis by-products and the fraction referring to the PnTx(19), which elutes with 29% buffer B.
  • the analysis by mass spectrometry MALDI-TOF
  • FIG 2 the mass expected for the peptide PnTx(19).
  • the LDH activity was evaluated in control conditions, in the presence of 1% Triton X-100 (100% of lysis) and in the presence of PnTx(19) in the following concentrations 10-5 M; 3x10-5 M; 10-6 M; 3.x10-6 M.
  • mice were sacrificed by decapitation, their penis were removed surgically and placed on a Petri dish containing Krebs Ringer bicarbonate - (NaCl, 118.1; KCl, 4.7; KH2PO4, 1.0; MgSo4, 1.0: NaHCO3, 25.0; CaCl2, 2.55; and Glucose, 11.1mM), bubbled with a mixture of 95% O2 and 5% CO2.
  • the gland, the spongy body and the urethra were removed and the cavernous bodies were desiccated with removal of the tunica albuginea and separated by cutting the fibrous septum between them.
  • the strips of cavernous bodies measuring about 1x1x7mm were mounted separately in a chamber, one end thereof being secured to an electrode and the other linked to a transducer.
  • the chambers contained Krebs (pH 7.4) at 37C, balanced with 95% O2 and 5% CO2.
  • the tissue was stretched by a passive force of 2.0 mN and stabilized for 60 minutes, the solution being replaced every 15 minutes.
  • the changes in isometric force were recorded by using an isometric force transducer (World Precision Instruments, Inc., Sarasota, FL, USA), connected to an amplifier (TBM-4 model; World Precision Instruments, Inc., USA), using software WinDaq Data Acquisition (Dada® Instruments, USA).
  • a KCI solution 120 mM was added to the slices of cavernous bodies and then the preparation was washed with Krebs three times.
  • the slices of cavernous body were pre-contracted with phenylfrin (100-5 M) and the relaxation was evoked by acetylcholine 10-4M (control), PntX2-6 (5x10-6M) and the peptide PnTx(19) (1x10-6M).
  • Figure 4 shows that the toxin PnTx2-6 (5x10-8 M) and the peptide PnTx(19) (10-6 M) induce relaxation of 83%, while the control with acetylcholine (10-4 M) induced 81.6% of relaxation on strips of cavernous bodies of mice pre-contracted by phenylfrin (10-5M).
  • L-glutamate The release of L-glutamate was analyzed according to the proposal of Nicholls et al. 1987 ( NICHOLLS, D. et al. J. Neurochem. 49, 5057, 1987 ). In order to evaluate whether the peptide was capable of inducing release of L-glutamate in cerebrocortical synoptosomes of rats, just as the native toxin, one analyzed the effect thereof at the following concentrations: 10-5M, 3x10-5M, 10-6M, and2x10-6 M, Figure 5 .
  • the rats were kept under a controlled cycle of 12 h light/darkness at a stable temperature with free access to water and food. They were decapitated 10 to 15 minutes after intraperitoneal injection of Heparin (200 IU).
  • the thorax was opened, the heart was carefully desiccated and perfused through an aortic tip with Krebs-Ringer solution (KRS) containing (by mmol/L) NaCl (118.4), KCI (4.7), KH2PO4 (1.2), MgSo4.7H2O (1.2), CaCl2.2H2O (1.25), glucose (11.7) and NaHCO3 (26.5).
  • KRS Krebs-Ringer solution
  • the perfusion flow was kept constant (10mL/min) at 37oC and under constant oxygenation (5% CO2 e 95% O2).
  • a balloon connected to a pressure transducer was inserted into the right ventricle, and one monitored the ventricular pressure, heart rate and derivative ⁇ dP/dt ( Figure 7 ).
  • the balloon volume was adjusted to a final diastolic pressure of about 10mm Hg.
  • 100 ⁇ mol/L carrier were injected (control), toxin at concentrations of 37.8 nmol/L - 3.78 ⁇ mol/L or a peptide at concentrations of 37.8 nmol/L - 37.8 ⁇ mol/L in perfusion buffer.
  • the toxin induced an increase dependent upon the concentration, under the final right ventricle systolic pressure (RFVSP/PVSFD) and in the +dP/dt, AND -dp/dt, at most by 66.7 ⁇ 13.55%, and 61.6 ⁇ 9.89%, respectively ( Figure 7 A; C and D).
  • the toxin did not alter the final diastolic pressure and the heart rate.
  • the peptide did not alter any of these parameters, even at high concentrations ( Figure 7B and E ).
  • mice 20-23 gram mice were divided into 2 groups (Control - Adjuvant: aluminum hydroxide - Figure 8A and PnTx-19 -10 ⁇ G - Figure 8B ), each group containing 4 animals.
  • the mice were immunized by subcutaneous route. 21, 35 and 49 days from the first inoculation, the mice received a reinforcement of the above-mentioned preparations.
  • the serum collected from the mouse tails was evaluated 15, 30, 40 and 60 days after the first inoculation through the indirect immunoenzymatic assay (ELISA), as described for other preparations ( DEL PINO, F.A.B., BRANDELLI, A., GONZALES, J.C., HENRIQUES, J.A.P., DEWES, H., Effect of antibodies against _-N-acetylglucosaminidase on reproductive efficiency of the bovine tick Boophilus microplus. Vet. Parasitol. 79, 247-255, 1998 ).
  • ELISA indirect immunoenzymatic assay

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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Claims (8)

  1. Peptide synthétique caractérisé en ce qu'il comprend la séquence GERRQYFWIAWYKLANSKK (SEQ ID NO : 1).
  2. Peptide synthétique selon la revendication 1, caractérisé en ce qu'il présente des modifications sur la partie N-terminale par acétylation et la partie C-terminale par amidation.
  3. Peptide synthétique selon la revendication 1, pour une utilisation en tant que médicament pour le traitement de sujets touchés par un dysfonctionnement de l'érection et/ou pour potentialiser la fonction érectile.
  4. Composition pharmaceutique caractérisée en ce qu'elle comprend le peptide synthétique représenté par la séquence SEQ ID NO : 1, et un excipient ou un mélange d'excipients pharmaceutiquement acceptables.
  5. Composition pharmaceutique selon la revendication 4, caractérisé en ce que le peptide est présent sous forme libre ou couplé à un système à libération contrôlée, choisi dans le groupe comprenant des liposomes, des cyclodextrines, des polymères biodégradables, des capsules, des micro- et nanocapsules, des micro- et nanoparticules, une préparation de bolus, des pompes osmotiques, des dispositifs de diffusion, des liposphères, des systèmes d'administration transdermique et/ou des liquides qui, lorsqu'ils sont soumis à des variations de température, forment un solide ou un gel in situ.
  6. Composition pharmaceutique selon la revendication 4 pour une utilisation en tant que médicament pour une administration par l'une ou l'autre des voies orale, topique, intramusculaire, intraveineuse, sous-cutanée et par inhalation, ou par un dispositif implantable.
  7. Composition pharmaceutique selon les revendications 4 et 5 pour une utilisation en tant que médicament pour le traitement d'individus touchés par un dysfonctionnement de l'érection et/ou pour potentialiser la fonction érectile.
  8. Composition pharmaceutique pour une utilisation selon la revendication 6 pour le traitement d'individus touchés par un dysfonctionnement de l'érection et/ou pour potentialiser la fonction érectile.
EP13831141.0A 2012-08-20 2013-08-20 Peptide synthétique pntx(19), compositions pharmaceutiques et utilisation Active EP2899198B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
BR102012020800A BR102012020800A2 (pt) 2012-08-20 2012-08-20 Peptídeo sintético pntx (19), composições farmacêuticas e uso
BR102013020574-5A BR102013020574B1 (pt) 2013-08-13 2013-08-13 PEPTÍDEO SINTÉTICO PnTx(19), COMPOSIÇÕES FARMACÊUTICAS E USO
PCT/BR2013/000319 WO2014028997A1 (fr) 2012-08-20 2013-08-20 Peptide synthétique pntx(19), compositions pharmaceutiques et utilisation

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EP2899198A1 EP2899198A1 (fr) 2015-07-29
EP2899198A4 EP2899198A4 (fr) 2016-01-20
EP2899198B1 true EP2899198B1 (fr) 2018-05-02

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US (1) US9279004B2 (fr)
EP (1) EP2899198B1 (fr)
JP (1) JP6430938B2 (fr)
KR (1) KR102103715B1 (fr)
CL (1) CL2015000415A1 (fr)
MX (1) MX362058B (fr)
PT (1) PT2899198T (fr)
WO (1) WO2014028997A1 (fr)

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KR101613302B1 (ko) * 2015-12-30 2016-04-18 (주)넥스젠바이오텍 Sv82 폴리펩타이드 및 이를 유효성분으로 함유하는 피부 주름 개선 및 탄력 유지용 화장료 조성물
KR101636851B1 (ko) * 2016-06-03 2016-07-06 (주)넥스젠바이오텍 피부 세포 증식 효과가 증가한 열 안정성 인간 상피세포성장인자-거미독 융합단백질 및 이를 유효성분으로 함유하는 피부 주름 개선 및 탄력 유지용 화장료 조성물
US10905738B2 (en) * 2018-07-05 2021-02-02 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Synthetic peptides, prodrugs, pharmaceutical compositions and uses
WO2021042193A1 (fr) * 2019-09-03 2021-03-11 Biozeus Desenvolvimento De Produtos Biofarmacêuticos Procédé et utilisation de pnpp-19 pour prévenir et traiter des maladies oculaires

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CL2007003884A1 (es) 2007-12-31 2009-09-25 Laboratorios Andromaco S A Péptido derivado del veneno de la araña viuda negra, procedimiento para preparar dicho péptido, composición farmacéutica que lo comprende, y uso de dicha composición para la preparación de un medicamente útil para el tratamiento de la disfunción sexual.
BRPI0800596A2 (pt) 2008-01-31 2009-09-22 Univ Minas Gerais método para a potencialização da função erétil através do uso das composições farmacêuticas de toxina tx2-6 da aranha phoneutria nigriventer

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MX362058B (es) 2019-01-07
JP6430938B2 (ja) 2018-11-28
EP2899198A4 (fr) 2016-01-20
PT2899198T (pt) 2018-06-29
US9279004B2 (en) 2016-03-08
CL2015000415A1 (es) 2015-09-11
WO2014028997A1 (fr) 2014-02-27
JP2015535808A (ja) 2015-12-17
KR20150084766A (ko) 2015-07-22
KR102103715B1 (ko) 2020-04-23
EP2899198A1 (fr) 2015-07-29
US20150218233A1 (en) 2015-08-06
MX2015002279A (es) 2015-10-15

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